Abstract. Pancreatic cancer is one of the most aggressive human malignancies, with a yearly incidence that equals its mortality. Radiation therapy (RT) is an integral component of modern therapy for locally advanced unresectable pancreatic cancers. However, its ultimate utility is severely limited by the fact that some cancer cells are resistant to RT. This problem is further amplified by the presence of gastrointestinal mucosa immediately adjacent to the tumor that makes dose escalation difficult and often not readily achievable. A novel approach to enhancing the radiation dose delivered to tumors is by transiently increasing the radiation-interaction probability of the target tissues using high atomic number (Z) nanomaterials. However, pancreatic cancer is characterized by hypovascularity in the setting of a dense stromal component that serves as a formidable physiological barrier to the delivery of drugs and nanoparticles. Therapeutic strategies, which can bypass the desmoplasia `fortress' and apply therapy without significantly affecting healthy cells and tissues would address the critical issues inherently presented by the pancreatic cancer. Here we propose to solve this delivery challenge by a paradigm shift from delivery of pre-made high-Z nanoparticles to an atomic size gold precursors (i.e., gold ions) for tumor radiosensitization thus achieving the ultimate reduction in size of a therapeutic agent ? an atomic scale. Our hypothesis is that small gold ions (i) will uniformly distribute throughout the tumor as their diffusion is not likely to be impeded by the stroma, and (ii) will be reduced to gold nanoparticles (GNPs) by cancer cells that (iii) will result in cancer cell radiosensitization to RT. This hypothesis is based on our compelling preliminary data demonstrating efficient synthesis of GNPs from gold ions inside pancreatic cancer cells but not normal cells. Further, the biosynthesized GNPs exhibited a high nuclear localization that is critical for efficient radiosensitization due to a higher dose delivery to nuclei by the secondary Auger electrons. In addition, a number of recent reports demonstrated intracellular synthesis of GNPs from chloroauric acid by mammalian cells with a preferential nuclear localization of the nanoparticles further supporting our hypothesis. Interestingly, this phenomenon has not been previously considered for applications in radiotherapy. We see it as a highly innovative and exciting opportunity to greatly improve radiosensitization efficiency of cancer cells in situ. We envision clinical implementation of our approach as an added boost to significantly increase efficacy of stereotactic body radiotherapy in patients with a pancreatic tumor. Recent clinical data from our group and others shows that radiation dose enhancement increases overall survival of locally advanced pancreatic cancer patients. However, the proximity of gastrointestinal mucosa to the tumor in many instances precludes this dose escalation in clinical practice. We expect that changing the current paradigm from delivery of pre-made GNPs to in situ synthesis of GNPs by cancer cells will overcame delivery barriers in pancreatic tumors and will result in a highly significant sensitization of pancreatic cancer cells to RT that can greatly improve treatment outcomes.